It is reported that pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. Pemetrexed works by inhibiting some enzymes used in purine and pyrimidine synthesis, such as thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells. The only version of this chemotherapy drug in the market currently is pemetrexed disodium (brand name Alimta) which is manufactured and marketed by Eli Lilly and Company, and used for the treatment of pleural mesothelioma and non-small cell lung cancer. Pemetrexed diacid is a critical precursor of the preparation of pemetrexed disodium. It is believed that pemetrexed diacid also has excellent anti-tumor activities as pemetrexed disodium. So far, many crystalline forms of pemetrexed diacid have been reported in several patents/applications. For example:
1) US2008045711A1 ('711 application) filed by Sicor, Inc. discloses seven crystalline forms of pemetrexed diacid including two crystalline forms of a hydrate (crystalline forms A and B), a crystalline form of a DMSO solvate (crystalline form C), two crystalline forms of a DMF solvate (crystalline forms D and E), and two anhydrous crystalline forms (crystalline forms F and G). US2011172424A1 discloses three crystalline forms of pemetrexed diacid and these crystalline forms are defined as a crystalline form of hydrate (crystalline forms H, I and J). Each of these crystalline forms has their inevitable shortcoming. For example, solvents incorporated in crystalline forms C, D and E have higher boiling points and can be difficult to remove, resulting in the increased burden of controlling the solvent residues during the preparation of a drug product. For the anhydrous crystalline forms F and G, a very high temperature (160-200° C.) is needed in the drying step, which may result in a greater risk of pemetrexed diacid degradation. The hydrate crystalline forms A and B also have their deficiencies during preparation. For example, the crystalline form A is difficult to filter which can result in a time-consuming operation and low yield. As to the crystalline form B, its crystallization period is very long and lacks efficiency. Specifically, up to about 18 hours are needed for the crystallization step alone.
2) US2011172424A1 ('424 application) filed by Chongqing Pharmaceutical Research Institute Co., Ltd. discloses three crystalline forms of hydrate (crystalline forms H, I and J). Among these crystalline forms, the yield of the crystalline form H is only about 60%. Further, the specification of the '424 application describes the method for preparing crystalline form H, wherein “pemetrexed diacid is directly dissolved in a mixed solvent consisting of water and water-miscible solvent.” The dissolution may be promoted by adjusting pH value or heating, wherein pH value is usually adjusted to pH 1-3 and heating is usually from 40° C. to near boiling point of the mixed solution. These conditions can be disadvantageous as heating a mixed solution at a high temperature for dissolution can result in development of unwanted discoloration that may require additional steps for color treatment. Crystalline form I, suffers from low yield. According to Example 5 ('424 application), if the water content of pemetrexed disodium (wet product) is assumed an optimized percentage (e.g., 10%), then the yield of pemetrexed diacid is only about 42.5%. As to the crystalline form J, Example 6 of the '424 application discloses that the mixture of pemetrexed disodium and water needs to be cooled to 0-5° C. After a pH adjustment, the reaction mixture was further stirred only for a short period of time (e.g., about 10 min). Regarding these operation conditions, one of ordinary skill in the art should be aware that the purpose of cooling the mixture of pemetrexed disodium and water to a low temperature and stirring the reaction mixture for a short period of time after a pH adjustment is to prevent a crystalline form from transferring to another known crystalline form, such as the crystalline forms A or B as disclosed in the '711 application. However, these procedures are not conducted under mild condition and may increase the operational difficulty of pemetrexed diacid preparation on a large scale.
Given the above, there remains a need in the art to develop other new crystalline forms of pemetrexed diacid in order to overcome the shortcomings of crystalline forms of pemetrexed diacid. Surprisingly, two novel crystalline forms of pemetrexed diacid have been identified that are stable and prepared easily on a large scale, and have good crystallinity.